The invention relates to methods for treating plasma kallikrein-related disorders, such as diseases or conditions associated with increased vascular permeability or astrocyte activation. Such diseases include diabetic retinopathy, macular edema, intracerebral hemorrhage, brain edema, and stroke.
Diabetic retinopathy (DR) is a well-characterized, sight-threatening, chronic ocular disorder that eventually develops to some degree in nearly all patients with diabetes mellitus (D M; Kempen et al., Arch. Ophthalmol. 122:552-563 (2004) and Williams et al., Eye 18:963-983 (2004)). Intensive glycemic and blood pressure control is associated with a delay in onset and a slowing of the progression of diabetic retinopathy. Nevertheless, DR is the leading cause of new cases of legal blindness among Americans between the ages of 20 and 74 years. The pathological changes associated with DR are similar in both type 1 and type 2 DM, although there is a higher risk of more frequent and severe ocular complications in type 1 diabetes mellitus (DM).
Diabetic retinopathy is characterized by gradual progressive alterations in the retinal microvasculature leading to areas of retinal non-perfusion, increased vasopermeability and pathologic intraocular proliferation of retinal vessels. The complications associated with the increased vasopermeability in the macula (termed macular edema) and uncontrolled neovascularization (termed proliferative diabetic retinopathy) can result in severe and permanent visual loss. After 15-20 years of DM, nearly all patients with type 1 DM and over 60% of those with type 2 DM will have some degree of retinopathy (Aiello et al., Diabetes Care. 21:143-156 (1998)). DR progresses in a predictable fashion through distinctly definable stages. It is divided into two broad categories, non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). These groups are further subdivided by level of severity. The risk of developing PDR, the most severe sight threatening form of retinopathy, increases as the level of NPDR increases (Early Treatment Diabetic Retinopathy Study Research Group, Ophthalmol. 98:766-785 (1991)).
Diabetic macular edema (DME) is a major cause of moderate visual loss and legal blindness in persons with type 2 diabetes (Javitt et al., Diabetes Care. 17:909-917 (1994)). DME can occur at any level of NPDR or PDR. Macular edema is the clinically evident accumulation of extracellular fluid in the retinal tissues of the macular area. In the United States alone, there are an estimated 500,000 people with DME and 325,000 with the more visually threatening clinically significant macular edema (CSME; Javitt et al., (1994); Javitt et al., Ophthalmol. 98:1565-1573 (1991); Javitt et al., Ann. Intern. Med. 124:164-169 (1996); Witkin et al., JAMA. 251:2534-2537 (1984)). An estimated 80,000 cases of DME and 56,000 cases of CSME occur each year as a result of diabetic retinopathy (Klein et al., Ophthalmol. 102:7-16 (1995); Javitt et al., Ophthalmol. 96:255-264 (1989)). The incidence of developing DME has been estimated from large epidemiological population-based surveys to be approximately 20-26% in type 1 patients (Klein et al., (1995); Klein et al., Ophthalmol. 105:1801-1815 (1998)), 25% in type 2 patients using insulin, and 14% in type 2 patients not requiring insulin (Klein et al., Ophthalmol. 102:7-16 (1995)).
Intracerebral hemorrhage (ICH) accounts for 10-15% of all cases of stroke and is associated with the highest mortality rate, with only 38% of affected patients surviving the first year (Dennis et al., Stroke 24:796-800 (1993)). The prognosis of ICH is poor, usually much worse than that of ischemic strokes of similar size (Pfohman et al., J. Neurosci. Nurs. 33:39-41 (2001)). Moreover, up to 30% of patients with ischemic stroke undergo hemorrhagic transformation (Lyden et al., Cerebrovasc. Brain Metab. Rev. 5:1-16 (1993)), and a number of patients with ischemic infarct after thrombolysis also develop hemorrhagic conversion (The NINDS t-PA Stroke Study Group, Stroke 28:2109-2118 (1997)). ICH generates neurological deterioration due to hematoma expansion and brain edema development (Brott et al., Stroke 28:1-5 (1997); Kazui et al., Stroke 28:2370-2375 (1997)). Hyperglycemia causes more profound brain edema, perihematomal cell death and a higher hemorrhagic transformation rate in experimental ICH (Song et al., Stroke 34:2215-2220 (2003); Demchuk et al., Stroke 30:34-39 (1999)). However, the precise mechanism of hematoma growth and edema formation after ICH is still unknown.
Stroke remains a leading cause of death and long-term disability in the United States. The increased risk of stroke has been linked to the pathophysiological changes seen in the cerebral vessels of individuals with diabetes (Kissela et al., Diabetes Care 28:355-359 (2005). In many epidemiological studies, type 2 diabetes mellitus (DM) has been an important risk factor for ischemic stroke (Almdal et al., Arch. Intern. Med. 164:1422-1426 (2004); however, only a few small studies have examined the risk of stroke in patients with type 1 DM during the past few decades. A recent study from the Nurses' Health Study, by investigating a very large cohort, reported that relative risks for total stroke was four-fold higher in women with type 1 DM and two-fold higher in women with type 2 DM than for non-diabetic (NDM) women. The multivariate relative risks of ischemic stroke was increased six-fold in type 1 and two-fold in type 2 DM. Moreover, type 1 DM was also significantly associated with the risk of hemorrhagic stroke (four fold), but type 2 DM was not (Janghorbani et al., Diabetes Care 30:1730-1735 (2007)).
Type 1 DM patients, especially those with a non-optimal metabolic control, have a higher risk of developing all microvascular complications including stroke (Kempen et al., Arch. Ophthalmol. 122:552-563 (2004)). Stroke is associated with decreased blood flow to the brain caused by a thrombus or rupture of a blood vessel. Moreover, thrombogenic stroke can undergo spontaneous hemorrhagic transformation, which can often be exacerbated by the combination of anticoagulation therapy. One of the outcomes of central nervous system damage caused by stroke is the breakdown of the blood-brain barrier (BBB) and increased local blood vessel permeability, which result in brain edema and neuronal and glial damage. Both clinical and experimental studies have shown that hyperglycemia has a deleterious effect on the BBB and causes edema formation after global ischemia or hemorrhage, however the mechanisms that mediate the adverse effect of diabetes and hyperglycemia on cerebral vascular function have received little attention (Williams et al., Eye. 18:963-983 (2004); The Diabetes Control and Complications Trial Research Group, N. Engl. J. Med. 329:977-986 (1993); Stratton et al., BMJ. 321:405-412 (2000); UK Prospective Diabetes Study Group, BMJ. 317:703-713 (1998)). Therapies to prevent or treat intracerebral hemorrhage remain a major unmet clinical need.